Total Synthesis of Gagunin E

• Applicant: Professor Dr. Martin Hiersemann
• Subject Area: Organic Molecular Chemistry - Synthesis and Characterisation
• Term: from 2020 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 437106685

The intricate structure of the unique marine diterpenoid gagunin E rests on a rare homoverrucosane scaffold of extraordinary molecular complexity. The molecular architecture of gagunin E is characterized by a pentahydroxylated and fourfold esterificated tricyclic AB-cis-BC-trans configured cyclohepta[e]hydrindane skeleton. This curved backbone is decorated by two angular methyl groups on the convex and an isopropyl group on the concave face. Furthermore, ten chirality centers in very close proximity are integral part of the homoverrucosane scaffold. Gagunin E exerts a significant biological activity (LC50 = 0.03 mg/mL, 49 nM, against the human myelogenous leukemia cell line K562) but access to the natural product from the natural source is severely limited (3 mg from 1.8 kg of the dried sponge). Here, we propose a research project aimed at the enantioselective total synthesis of gagunin E. Several key objectives will be addressed, for instance: (i) we envision to establish an unprecedented variant of a H(ydroxyl)D(directed)D(iels)A(alder) reaction to assemble the pivotal AB-cis hydrindanoid segment of gagunin E; (ii) we intend to assign the currently unknown absolute configuration of gagunin E by total synthesis; (iii) we will continue our collaborative efforts to explore the MDR modulating properties of gagunin E and its derivatives; (iv) we are seeking to launch collaborative efforts to shed light on the molecular mode of action of gagunin E against K562, embarking with the working hypothesis that gagunin E represents a Bcr-Abl tyrosine-kinase inhibitor.

• DFG Programme: Research Grants